As techniques for improving the absorption of a poorly water soluble substance from the gastrointestinal tract and suppressing the variation thereof, solubilization by the addition of cyclodextrin and the like, solid dispersion and micronization are known (International Patent Publication Nos. WO96/019239 and WO02/048142). Hence, it is known that poorly water soluble substance is micronized to improve the absorption of a poorly water soluble substance and to suppress the variation in the absorption. However, as a method of micronizing a poorly water soluble substance, dry pulverization using jet mill and the like is commonly used; in the dry pulverization, because the surface area increases with the progress of pulverization, resulting in re-aggregation, it is difficult to micronize a poorly water soluble substance until the median diameter becomes not more than several microns (that is, the particle size reached is up to several microns as the median diameter).
On the other hand, to obtain microparticles not more than several microns, it is common practice to use a build-up method such as crystallization, wherein particles are formed from a dissolved state with gradually increasing sizes. However, in build-up methods such as crystallization, because it is usually necessary to dissolve the poorly water soluble substance once in a good solvent such as an organic solvent, and then add the solution to a poor solvent, various crystallization conditions must be carefully evaluated for each kind of poorly water soluble substance to be micronized, which involves complicated operation. Also, because a poorly water soluble substance micronized by the build-up method to the extent that makes the median diameter to be not more than several microns is microcrystalline unlike in the crystallization operation for preparing macrocrystals for purification, the solvent and the like used are likely to remain as residues. It is hard to obtain pure microparticles. Particularly, when the build-up method is used in the pharmaceutical field, there is a problem in which if a solvent other than water remains as a residue, the residual amount must be measured and safety must be assured.
Also, wet pulverization usually enables pulverization to finer particle sizes than dry pulverization, but because the pulverization performance differs depending on the choice of dispersion stabilizer and the amount added, it is necessary to carefully evaluate the pulverization formula (choice of dispersion stabilizer and the amount added) for each kind of poorly water soluble substance. Even when the pulverization formula is prepared, it is not always easy to micronize the formulation to the extent that the median diameter is not more than several microns; it has been substantially difficult to sufficiently improve the absorption of a poorly water soluble substance or suppress the variation in the absorption.
In view of the above-described situation, the present invention is intended to provide a micronized composition comprising a poorly water soluble substance wherein the poorly water soluble substance is sufficiently micronized to improve the absorbability of the poorly water soluble substance (preferably absorption is improved and variation in absorption is suppressed), and a method of producing the same, and a use thereof.